Discovery of 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating of chronic kidney diseases

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 2; pp. 565 - 570
• Main Authors: Kato, Yuko, Fuchi, Nobuhiro, Nishimura, Yutaka, Watanabe, Ayano, Yagi, Mai, Nakadera, Yasuhito, Higashi, Eriko, Yamada, Masateru, Aoki, Takumi, Kigoshi, Hideo
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.01.2014; Elsevier
• Subjects: Administration, Oral; Alkanes - administration & dosage; Alkanes - chemistry; Animal models; Animals; Anti-GBM glomerulonephritis rat model; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Chronic kidney diseases; Drug Discovery - methods; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - metabolism; Humans; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Rats; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - enzymology; Science & Technology; sEH inhibitor; Solubility; Spirocyclic diamine; Structure-Activity Relationship; Urea; Urea - administration & dosage; Urea - analogs & derivatives; Urea; sEH inhibitor; Spirocyclic diamine; Anti-GBM glomerulonephritis rat model; Chronic kidney diseases; METABOLISM; ACIDS; HYPERTENSION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.12.020

We identified 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted ureas as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating chronic kidney diseases. Compound 19 exhibited excellent sEH inhibitory activity and bioavailability. When administered orally at 30mg/kg, 19 lowered serum creatinine in a rat model of anti-glomerular basement membrane glomerulonephritis but 2,8-diazaspiro[4.5]decane-based trisubstituted ureas did not. These results suggest that 19 is an orally active drug candidate for treating chronic kidney diseases.